There have been many approaches to meet the problems of regulating the delivery of bioactive agents, such as drugs, to biological systems including humans, to achieve a proper dose and/or a desired effect. In the prior art, successful bioactive agent delivery vehicles have been designed that are capable of maintaining the bioactive agent in its dissolved state over an extended storage period, and the bioactive agent delivery vehicle itself has been designed to remain stable over a predetermined storage period. Commonly employed delivery vehicles for bioactive agent delivery include lipid emulsions and microemulsions, as well as liposomes and lipospheres compositions.
Emulsion particle or droplet sizes can range from about 200 nm to 1,000 nm. In the prior art, particle size of the lipid emulsions has precluded the use of filters to sterilize such compositions, and thus, heat sterilization has been used. A drawback of the use of heat sterilization is that it can be detrimental to various bioactive agents. Additionally, from a manufacturing standpoint, emulsions have not been preferred for use due to the requirement of the use of the high shear equipment that is presently known, and because emulsions suffer from physical stability problems such as creaming and cracking.
Microemulsions have also been used as bioactive agent delivery compositions. Microemulsions are generally defined as those systems containing a lipophilic and a hydrophilic component wherein the average particle size of the dispersed phase is below about 200 nm. Microemulsions are further characterized as being clear or translucent preparations. The clarity and particle size characteristics distinguish microemulsions from emulsions. The smaller particle size range of microemulsions enables them to be retained in the blood system for a longer period of time than emulsions. Microemulsions are typically more physically stable than emulsions and seldom suffer from creaming or cracking problems, but these phase separation problems may occur during storage under certain conditions.
Liposomes are microscopic vesicles having single or multiple lipid bilayers that can entrap hydrophilic compounds within their aqueous cores. Polar (including hydrophilic) and nonpolar (including hydrophobic) compounds may partition into lipid bilayers. Liposomes have been formed in sizes as small as tens of Angstroms to as large as a few microns, and can be carriers for bioactive agents. Typically, liposomes have been prepared by sonication, detergent dialysis, ethanol injection, French press extrusion, ether infusion, and reverse phase evaporation. These methods often leave residuals such as detergents or organics with the final liposome. Many liposome products are not stable for long periods of time.
Present liposome products can be difficult to sterilize. Sterility is currently accomplished by independently sterilizing component parts (including the lipid, buffer, bioactive agent, and water) such as by the use of an autoclave or by filtration, and then mixing in a sterile environment. This sterilization process can be difficult, time consuming, and expensive since the product must be demonstratively sterile after several processing steps and these methods are not convenient in a retail pharmacy, a doctors office, or in a patients home. Further, sterilizing a formed liposome is usually not feasible as autoclave sterilization can denature the liposome, and filtration can alter the features of multilayered liposomes.
Ink-jet pens have primarily been used in the prior art to form precise patterns of dots in the form of ink-containing images. An ink-jet pen acts by ejecting fluid from a drop-generating device known as a “printhead” onto a printing medium. The typical ink-jet printhead has an array of precisely formed nozzles located on a nozzle plate and attached to an ink-jet printhead substrate. The substrate incorporates an array of firing chambers that receive liquid ink (colorants dissolved or dispersed in a solvent) through fluid communication with one or more ink reservoirs. Each chamber can have a thin-film resistor, known as a “firing resistor,” located opposite the nozzle so ink can collect between the firing resistor and the nozzle. The printhead is held and protected by outer packaging referred to as a print cartridge, i.e., ink-jet pen. Upon energizing of a particular resistor element, a droplet of ink is expelled through the nozzle toward the print medium, whether paper, transparent film or the like. The firing of ink droplets is typically under the control of a microprocessor, the signals of which are conveyed by electrical traces to the resistor elements, thereby forming alphanumeric and other characters on the print medium. In the prior art, various emulsion techniques have been implemented in ink-jet ink applications, e.g., both oil-in-water (O/W) and water-in-oil (W/O).